Transdermal devices for delivery of a variety of biologically active agents through the skin or mucosa are known to the art. Representative systems which use rate controlling membranes and in-line adhesives (i.e., adhesives disposed in the path of drug or agent migration from the reservoir to the skin) are disclosed in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,742,951; 4,031,894; 4,060,084; 4,144,317; 4,201,211; and 4,379,454. Subsaturated transdermal devices are disclosed in U.S. Pat. No. 4,379,454. U.S. Pat. No. 4,286,592 describes a transdermal drug delivery device in which the PIB/MO adhesive is less permeable to the drug being delivered than is the reservoir layer. The limited permeability adhesive layer acts as a rate-controlling member.
When in-line adhesives are used in transdermal delivery devices it is necessary that they exhibit a reasonable permeability to the agent being delivered and, when they are used in combination with a rate-controlling membrane, the adhesive layer preferably exhibits a higher permeability to the drug than the rate controlling membrane.
Mixtures of high and low molecular weight polyisobutylenes (PIB) are known to the art as adhesives, however they are relatively impermeable to many drugs. As a result, the prior art in-line PIB adhesives usually contain a plasticizer such as mineral oil (MO) or polybutene to achieve sufficient permeability to permit drug migration through the adhesive at rates which are therapeutically useful from reasonably sized systems.
A typical formulation of the prior art uses a ratio of 1.2M molecular weight (MW) PIB:35K MW PIB:MO of about 1:1.125:2. In such a formulation the high molecular weight (HMW) PIB acts as an adhesive base, the low molecular weight (LMW) PIB acts as tackifier, and the mineral oil acts to plasticize the adhesive and to increase the permeability of the adhesive composition to the drug.
It is also known to include tackifiers to improve the adhesive characteristics of medical adhesives. For example, Australian application AU-A-57457/86 discloses a self adhesive matrix for delivering nitroglycerin which comprises a mineral oil-free mixture of high and low molecular weight PIB's with a resinous tackifier. Such tackifiers are often natural resinous or rosinous products of undefined compositions. Both mineral oil and tackifiers vary in their detailed composition from batch to batch and may unpredictably contain components which are irritating or sensitizing to the skin.
Many medically acceptable contact adhesives of the prior art are ineffective in the transdermal delivery of active agents which are highly soluble in the adhesives. When the agent has a high solubility in the adhesive layer, substantial quantities of agent migrate from the reservoir through the rate controlling membrane and into the adhesive layer as the device equilibrates over time. The migration continues until the thermodynamic activity of the agent in the adhesive equals the thermodynamic activity of the agent in the reservoir. As a result, the large quantity of the active agent in the adhesive layer is released onto the skin without control by the rate controlling membrane, which can only exert an effect on the agent which remains in the reservoir. High concentrations of agent in direct contact with the skin can also cause irritation, or produce undesirably high initial plasma levels of the agent.
Many medically acceptable contact adhesives of the prior art are also ineffective in conjunction with agents which are capable of plasticizing, solvating, or otherwise causing the adhesive to lose its cohesiveness. Such agents, which are typically oily, non-polar components such as nicotine, benztropine, secoverine, dexsecoverine and arecoline, for example, can destroy the adhesive properties of a transdermal patch, causing premature detachment of the system. U.S. Pat. Nos. 4,597,961 and 4,839,174, the disclosures of which are incorporated herein by reference, disclose transdermal nicotine delivery devices in which nicotine is present in the reservoir. The device of U.S. Pat. No. 4,597,561 uses a peripheral adhesive to avoid this type of problem. Copending, commonly assigned U.S. application Ser. No. 07/206,546, filed Jun. 14, 1988 now abandoned, the disclosure of which is incorporated herein by reference, describes a transdermal nicotine delivery system using a subsaturated reservoir to cope with this problem.
Mineral oil is also soluble in some common components of transdermal systems, such as ethylene vinyl acetate copolymers (EVA) and may migrate from the adhesive layer into these materials over time. The loss of the plasticizing mineral oil in the adhesive can cause changes in the physical properties of the adhesive compound, adversely affecting the performance of the adhesive.
According to our invention, it has unexpectedly been discovered that certain agents, in the presence of which traditional transdermal non-PIB adhesives are plasticized, solvated, or lose their adhesive properties, can be delivered from a transdermal delivery device using the in-line PIB adhesives of this invention which are substantially free of tackifiers and plasticizers.
It is therefore an object of this invention to provide a new and useful in-line adhesive for use in transdermal delivery devices.
It is another object of this invention to provide in-line adhesives for transdermal delivery devices which are useful in delivery of agents which have an undesirably high solubility in prior in-line adhesives.
It is another object of the invention to provide a PIB adhesive substantially free of plasticizers and tackifiers.
It is yet another object of this invention to provide an in-line adhesive in a transdermal delivery device which rapidly reaches equilibrium after manufacture.
It is yet another object of the invention to provide a transdermal delivery system using high and low molecular weight PIB substantially free of plasticizers and tackifiers, as an in-line adhesive.
It is another object of this invention to provide PIB adhesives substantially free of plasticizers and tackifiers having a high permeability for the agent to be delivered, and which are suitable as an in-line adhesives in transdermal delivery devices having a release rate controlling membrane.
It is another object of this invention to provide an in-line adhesive for use in a transdermal delivery device which is relatively non-irritating, is inexpensive, can be used in the delivery of oily, non-polar active agents.